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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Reduction of serum lipids by liver-specific knockout of chemerin in DIO mice
1Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases & Department of Biochemistry, School of Medicine, Sun Yat-sen University, Shenzhen, 518107, China.
Insights
Chemerin, an adipokine, drives hyperlipidemia in obesity. Targeting liver chemerin (encoded by Rarres2) reduces high cholesterol and triglycerides, offering a new therapeutic strategy for cardiovascular disease risk.
Area of Science:
- Biochemistry
- Cardiovascular Medicine
- Metabolic Diseases
Background:
- Cardiovascular diseases (CVDs) are a leading cause of death globally.
- Hyperlipidemia is a critical risk factor for CVDs.
- Current lipid-lowering therapies have limitations, necessitating novel therapeutic targets.
Purpose of the Study:
- To investigate the role of chemerin, an adipokine, in the pathogenesis of dyslipidemia.
- To explore chemerin as a potential therapeutic target for hyperlipidemia.
Main Methods:
- Clinical analysis of 42 treatment-naive participants correlating serum chemerin with lipid profiles.
- Administration of exogenous chemerin to C57BL/6J mice on a high-fat diet (HFD).
- Liver-specific Rarres2 (chemerin-encoding gene) knockout in mice using AAV9-CRISPR.
Main Results:
- Serum chemerin positively correlated with triglycerides, total cholesterol, and LDL-C in humans.
- Exogenous chemerin increased serum TG, TC, and LDL-C in HFD-fed mice.
- Liver-specific Rarres2 knockout reduced HFD-induced hyperlipidemia, hepatic injury, and systemic inflammation.
Conclusions:
- Chemerin is a hepatic mediator of obesity-related hyperlipidemia.
- Targeting liver chemerin represents a promising therapeutic strategy for hyperlipidemia and associated cardiovascular risks.
Abstract:
Cardiovascular diseases (CVDs) remain the leading global cause of death, with hyperlipidemia being a critical risk factor. Current lipid-lowering therapies (e.g., statins, PCSK9 inhibitors) effectively reduce LDL-C but have limitations like side effects or residual cardiovascular risk, necessitating novel therapeutic targets. In this study, we aimed to explore the role of chemerin, an adipokine, in the pathogenesis of dyslipidemia. Clinical analysis of 42 treatment-naive participants showed significant positive correlations between serum chemerin and triglycerides (TG, R2 = 0.5073, p < 0.0001), total cholesterol (TC, R2 = 0.1464, p = 0.0124), and LDL-C (R2 = 0.1600, p = 0.0087), independent of HDL-C. In C57BL/6J mice, exogenous chemerin administration in high-fat diet (HFD)-induced obesity models significantly increased serum TG, TC, and LDL-C levels. Moreover, we found that the expression of chemerin was upregulated in liver (but not adipose tissues) of obese mice, which indicates that the liver is the primary source of obesity-associated chemerin. The animal experiments showed that liver-specific Rarres2 (chemerin-encoding gene) knockout via AAV9-CRISPR reduced HFD-induced elevations of serum TG, TC, and LDL-C levels. Furthermore, the results showed that liver-specific Rarres2 knockout also ameliorated hepatic injury (ALT, AST) and systemic inflammation (TNF-α, IL-6). Collectively, these findings establish chemerin as a hepatic mediator of obesity-related hyperlipidemia, supporting its potential as a therapeutic target for hyperlipidemia.
